The seasonal burden of influenza, coupled with the with the recent pandemic outbreaks of more pathogenic strains such as the 2009 and 2013 H1N1, underscores the critical need for understanding the pathophysiology of influenza injury. Vaccination remains a cornerstone in the prevention of infection. However, vaccine efficacy varies from 50-80 % in a healthy population and can be even lower in very young children, elderly populations and the immune compromised. Therefore, there is critical need for effective therapeutic regimens focused on reducing viral burden, decreasing inflammation and promoting lung/epithelial repair. We have recently identified IL-22 as an epithelial specific cytokine that i integral in lung epithelial repair. However, mechanisms through which it promotes lung repair are unresolved. The central hypothesis for this application is IL-22 production ameliorates both airway injury as well as diffuse alveolar destruction (DAD) after influenza induced injury. We hypothesize that IL-22 interacts directly on epithelial cells, reducing apoptosis and promoting epithelial migration, which in turn, reduces inflammation. Our rationale is that mice lacking IL-22 have defects in epithelial repair and decreased numbers of lung progenitor cells. Importantly, administration of IL-22 reduces injury and rescues mice from fatal influenza infection. Thus, IL-22/IL-22RA1 signaling can be exploited therapeutically to reduce lung injury during experimental influenza infection. This hypothesis will be tested by pursuing three specific aims. In the first am we will test the role of IL-22 in ameliorating airway injury and promoting epithelial repair of the upper and lower conducting airways. We will test this by utilizing IL-22Ra1fl/fl crossed to airway and epithelial specific cre lines. We will examine the protective role of IL-22 using airway specific IL-22 transgenic mouse, and examine the effects in an uninhibited environment using IL-22BP-/- mice. Finally we will determine the therapeutic/reparative effects by administering IL-22:Fc at different times after infection and examining airway repair. The second aim will test our hypothesis that IL-22 signals through AKT and both canonical and non-canonical STAT3 pathways, using in vitro techniques in both human and mouse airway cells. The third aim specific aim is designed to test the ability of IL-22 to reduce DAD by communicating with lung progenitor cells. We will study the interaction of IL-22 in alveolar repair through the use of our IL- 22Ra1floxed mice crossed with epithelial and progenitor cell specific cre lines. Further, the ability of IL-22 to induce progenitor cell populations in repair will be examined, as well as the therapeutic use of IL-22 during influenza induced DAD. The contribution of the project outlined here is to provide a detailed understanding of how IL-22 promotes epithelial repair in both the airways and lung parenchyma after injury. To our knowledge, there are no studies identifying cytokine/stem cell interactions in the lung during disease. Such studies would provide novel insight into how inflammatory cells promote epithelial repair and have potentially great impact on influenza as well as a number of diseases involving parenchymal injury such as IPF and COPD.